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SCREENING OF DRUGS USED IN ANTIARRYTHMIA

This document summarizes information about cardiac arrhythmias. It begins with an introduction defining arrhythmia as a deviation from the heart's normal rhythm. It then discusses normal heart rhythm and the cardiac action potential in detail. It describes several mechanisms that can cause arrhythmias, including enhanced pacemaker activity, after-depolarizations, and reentry. It classifies arrhythmias and lists symptoms. Several in vitro and in vivo models for evaluating antiarrhythmic drugs are presented, including the Langendorff technique, acetylcholine-induced arrhythmias, chemically-induced arrhythmias in rats, digoxin-induced arrhythmias in guinea pigs, and exercise-induced arrhythmias in dogs

Education◦
PRESENTED BY : SREYA. S M. Pharmacy Academic year:2019-2021 DEPT OF PHARMACOLOGY
INTRODUCTION  Arrhythmia is deviation of heart from normal RHYTHM. Abnormality in the origin, rate, rhythm, conduction velocity and sequence of heart activation. It may cause sudden death or syncope, heart failure, dizzines, palpitations, or no symptoms at all. RHYTHM 1) HR- 60-100 2) Should origin from SAN 3) Cardiac impulse should propagate through normal conduction pathway with normal velocity.
Cardiac Action Potential  When the stimulus reach the cardiac cell,specific ions moves into and out of the eliciting the action potential cell. Such movement of ions is divided into following or phases:
 Phase 0: rapid depolarization of cell membrane during which theirs is fast entry of Na ions into the cells through Na channels, this is followed by repolarization.  Phase 1: is short initial rapid repolarization due to Ka efflux  Phase 2: prolonged plateue phase due to slow Ca influx  Phases 3: rapid repolarization with Ka efflux  Phase 4: resting phase during which Ka ions return into the cell while Na and Ka move out of it and resting membrane potential is stored
Mechanisms of cardiac arrhythmias •Enhanced/ectopic pacemaker activity •After-depolarizations • Reentry Enhanced/ectopic pacemaker activity – Ectopic impulse may also result from current of injury. The slope of phase4 depolarization may be increased pathologically in the automatic fibres
 After-depolarizations – Early after-depolarization (EAD) – Delayed afterdepolarization (DAD  Reentry – Primarily due to abnormality of conduction, an impulse may recirculate in the heart and cause repetitive activation without the need for any new impulse to be generated. These are called reentrant arrhythmias.
CLASSIFICATION OFARRHYTHMIAS 1. Characteristics: a. Flutter – very rapid but regular contractions b. Tachyarrhthmia – increased rate c. Bradyarrhythmia – decreased rate d. Fibrillation – disorganized contractile activity  500 Atrial fibrillation  350 Atrial flutter  200 Paroxysmal TA  100-60-Normal range  40 Mild bradyarrhythmias  20 moderate BA
 Atrial flutter (AFL) [can be regular or irregular] is an abnormality of conduction within the atria. The atria beat more frequently than the ventricles (up to 300 bpm).  Atrial Fibrillation (AF) [always irregular] there is a complete absence of a Sino-Atrial stimulus which would result in a P wave. The atria beat out of coordination ventricle). This leads to a rapid and irregular heart rhythm. In AF, the heart rate ranges from 100 to 175 bpm.
SYMPTOMS  Noticeable arrhythmia symptoms may include: A fluttering in your chest. A racing heartbeat (tachycardia) A slow heartbeat (bradycardia)  Can have no symptoms, but people may experience:  Pain areas: in the chest  Whole body: dizziness, fainting, or light-headedness  Heart: palpitations or slow heart rate  Also common: shortness of breath
Evaluation of Anti arrhythmic Drug Action In-Vitro Models: 1) Langendorff technique 2) Acetylcholine & potassium Induced arrythmia In Vivo Models 1) Chemically induced arrhythmia 2) Electrically induced arrhythmia 3) Exercise Induced Arrhythmia 4) Mechanicallyinducedarrhythmia
LANGENDORFF TECHNIQUE PRINCIPAL Basic principal involved is that heart is perfused in RETROGRADE Direction from aorta either at constant pressure or constant flow with oxygenated saline solution. It closes aortic valves, just in situ heart during diastole. The perfusate is displaced through the coronary sinus and the opened right atrium. Animal Used – Guinea pig (300- 500g)
PROCEDURE Animal – Guinea pig (300-500g) Animal is selected ,then it is Sacrificed (stunning) the heart is removed and placed in Ringer’s solution (37⁰C).  The Aorta is located and cut . Then cannulated with Ringer’s solution (perfused at 40 mm Hg) . The Ligature – placed around LAD  Test /std/control - administered. Then it is Occluded for 10 minutes ,reperfused.  ECG electrode – pulsatile stimulation, induction of arrhythmia  Heart rate and contractile force measured
EVALUATION Heart rate measured through chronometer coupled to polygraph, Contractile force measured by force transducer. Incidence and duration of ventricular fibrillation or ventricular tachycardia is recorded in the control as well as test group.
Acetylcholine or Potassium Induced Arrhythmias PRINCIPLE The K+ channel function determines membrane potential and refractoriness of the myocardium. Both gain and loss of the K+ channel function can lead to arrhythmia Animal used- New Zealand white rabbits (0.5-3kg)
PROCEDURE  New Zealand white rabbits (0.5-3kg) sacrificed and heart removed  Atria dissected from other tissue in RL and attached with electrode  Fibrillation produced when atria exposed with Acetylcholine or KCL  After 5min exposure to Acetylcholine or KCL, atria stimulated with pulses 0.75 ms , usually of 10V and recorded on Kymograph  Control arrhythmia produced for 6-10 min followed by 30 min rest period  Test compound were added to the bath
EVALUATION  Test drug found to be effective If fibrillation is isdisappears immediately or within 5min  If fibrillation doesn't disappear within 8-10 min, preparation is washed to allowed to normal concentration
IN VIVO MODELS Chemically Induced Arrhythmia ACONITINE ANTAGONISM IN RATS Priciple Aconitine, its plant alkaloid from roots, it Acts perstintant on Na+ channels resulting ventricular arrhythmias Animal used: Male Ivanovas rats (300-400 gm) Procedure: Male Ivanovas rats (300-400 gm) anesthetized intraperitonially with urethane (1.25 g/kg) Aconitine dissolved (5 mcg/kg) in 0.1 N HNO3 & infused into rat’s saphenous vein @ 0.1 ml/min Lead II ECG is recorded every 30 sec.
 Test compound injected orally 5 min before Aconitine infusion  Higher dose of aconitine in the test group gives an index of antiarrhythmic activity.  The antiarrhythmic effect of test compound is measured by the amount of aconitine /100g animal  Higher dose of aconitine is needed as compared with control group Evaluation  The anti-arrhythmic effect of the test compound is measured by the amount of aconitine/100 gm animal (infusion duration ), required to precipitate... Ventricular extra systoles. Ventricular tachycardia. Ventricular fibrillation and death
DIGOXIN INDUCED ARRHYTHMIA IN GUINEA PIGS  PRINICPLE: Over dose of cardiac glycosides induces ventricular extrasystoles, ventricular fibrillation, and finally death. Animal used:male guinea pigs.(Marioth 350-500 gms) Standard drugs : lidocaine 3 mg/kg iv Procedure:  Anesthetised male guinea pigs.(Marioth 350-500 gms)  Trachea, jugular vein and carotid artery are catheterized.  Test grp receives Test drug either orally 1 hr or iv 1 min prior to the infusion while controlol group receieves digoxin infusion only at rate of 85 mg / kg in 0.266 ml/min. until cardiac arrest occurs.  Lead III ECG recorded
Evaluation  The period until the onset of ventricular extra systoles, ventricular fibrillation and cardiac arrest is recorded  Using Student’s t-test the doses of digoxin needed to induce VES, VF and Cardiac arrest respectivelyafter treatment with aniarrhythmic drugs are compared with control receiving digoxin only
ELECTRICALLY INDUCED ARHYTHMIAS VENTRICULAR FIBRILLATION ELECTRICAL THRESHOLD Principle Ventricular fibrillations can be induced by various tec. Of electrical stimulation like single pulse stimulation , train of pulse stimulation , continous 50 HZ stimulation  Ventricular fibrillation threshold :The minimal current intensity of the pulse train required to induce sustained ventricular fibrillation. Animals – Adult dogs (8-12kg) Anesthetic – Sodium pentobarbital (35mg/kg)
PROCEDURE  Dogs (8-12 kg) anesthetized with pentobarbitone intraperitonially and maintained on artificial respiration  Chest opened & heart is suspended on pericardial cradle  SA node crushed & Ag-AgCl stimulating electrode embedded with Teflon disc sutured to anterior surface of LV  Anodal constant current for 400ms is applied through electrode and which was programmed by digital stimulator  ECG recorded through lead II of body ECG monitoring  To determine Ventricular Fibrillation (VFT) 0.2 to 1.8 s train of 50Hz pulses delivered  The current intensity of pulse train required to induce sustained ventricular fibrillation is define as VFT
When VF occurs, heart immediately defibrillate & allow to recover as controlled condition for 15-20 min Test drug administered through femoral vein EVALUATION  VFT is determined before and after administration of test drug & compared by using student T-Test
EXERCISE INDUCED ARRHYTHMIA EXERCISE INDUCED VENTRICULAR FIBRILLATION PURPOSE AND RATIONALE: Tests combining coronary constriction with physical exercise may resemble most closely the situation in coronary patients Animals – Mongrel dogs (15 -19 kg) Anesthetic – Sodium pentobarbitone (10mg/kg) i.v.
PROCEDURE Animals IS selected. IT IS Anesthetized . The Chest cavity is opened .  Heart suspended in pericardial cradle . Around left circumflex artery – Doppler flow inducerto measure blood pressure - Hydraulic occluder - to occlude coronary artery are placed  A Pair of insulated silver coated wires – sutured on left and right ventricles- measure HR (By Gould biotachometer) . The Occlusion of LAD(Two stage) . Myocardial infarction . After 24 hrs- test drug/std/control - administered
 3-4 weeks after the production of MI .The Animals run on a motor driven treadmill at speed 6.4 km/hr (o%) grade.  Work load increasesa every 3 min for total of 18 mins(0,4,8,12,16%) .During last minute-treadmill is stopped- left circum flex arteryoccluded for additional 1 min.  After 10-20 sec of VF – defibrillation is achieved without any delay by placing large metal plates across animal’s chest.  X
 Protocol starts with 3 min warm up followed by run @ 6.4 km/hr (0 % grade)  Grade is increased every 3min run 0% 4% 8% 12% and 16%  During last min of exercise LCX is occluded, treadmill stopped & occlusion maintained for additional 1min  Occlusion is released if VF occurs  Exercise and ischemia test is repeated after pretreated with test drug & compared with control reading
EVALUATION: The exercise plus ischemia test is repeated after administration of the test drug and compared to control (saline) group.The effect of drugs intervention on arrhythmia formation are determined using chi square test with yates correction.
MECHANICALLYINDUCEDARRHYTHMIA CORONARY ARTERY OCCLUSION/REPERFUSION ARRHYTHMIA PRINCIPLE ; Arrhythmias –induced directly by ischemia and reperfusion Animals Used– Dogs (20-25Kg) Anesthetic – Thiobutobarbital sodium (30mg/kg) PROCEDURE:  Animals is selected . Then its is anesthetized Artificial respiration is given by positive pressu respirator. Femoral artery iscannulated and connected to pressure transducer . The Chest cavity is opened and LAD is exposed
 Silk suture is placed around LAD.After 45 min(equilibration) – test/std/control- administered through saphenous vein  After 20 min- ligature of coronary artery is closed for 90 min  Occlusion released – reperfusion period maintained for 30 min.  All the parameters – recorded  At the end – surviving animals are sacrificed by an overdose of Pentobarbital sodium. EVALUATION • Mortality , Hemodynamics, Arrhythmia • Ventricular fibrillation • % animals with VF.
REFERENCES  Vogel WH, Schölkens BA. Drug Discovery and Evaluation [Internet]. Springer Berlin Heidelberg; 2002. P.208-29.  Essentials of medical pharmacology –KD Tripathi
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